The involvement of kinases in the development of cancer is well known. For example, kinases known to be associated with tumorigenesis include the Raf serine/threonine kinases and the receptor tyrosine kinases (RTKs). Both types of kinases are part of a signal transduction pathway which ultimately phosphorylates transcription factors. Within the pathway, Raf kinases are part of the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling module that influence and regulate many cellular functions such as proliferation, differentiation, survival, oncogenic transformation and apoptosis.
Several Raf kinase inhibitors have been described as exhibiting efficacy in inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other patents and patent applications suggest the use of Raf kinase inhibitors for treating leukemia (see, e.g., U.S. Pat. Nos. 6,268,391, and 6,204,467, and published U.S. Patent Application Nos. 20020137774; 20020082192; 20010016194; and 20010006975), or for treating breast cancer (see, e.g., U.S. Pat. Nos. 6,358,932; 5,717,100; 6,458,813; 6,268,391; and 6,204,467, and published U.S. Patent Application No. 20010014679). In early clinical trials, inhibitors of Raf-1 kinase that also inhibit B-Raf have shown promise as therapeutic agents in cancer therapy (Crump, Current Pharmaceutical Design 8:2243-2248 (2002); Sebastien et al., Current Pharmaceutical Design 8: 2249-2253 (2002)).
Receptor tyrosine kinases (RTKs), such as vascular endothelial growth factor receptors (VEGFR), are transmembrane polypeptides that regulate developmental cell growth and differentiation, remodeling, and regeneration of adult tissues. Mustonen, T. et al., J. Cell Biology 129:895-898 (1995); van der Geer, P. et al., Ann Rev. Cell Biol. 10:251-337 (1994). VEGF and members of the VEGF subfamily are able to induce vascular permeability and endothelial cell migration and proliferation, as welt as induce angiogenesis and vasculogenesis, Ferrara, N. et al., Endocrinol. Rev. 18:4-25 (1997); Connolly, D. et al., J. Biol. Chem. 264:20017-20024 (1989); Connolly, D. et al., J. Clin. Invest. 84:1470-1478 (1989); Leung, D. et al., Science 246:1306-1309 (1989); Plouet, J. et al., EMBO J 8:3801-3806 (1989).
Angiogenesis is the process whereby new blood vessels are formed in a tissue, and is critical to the growth of cancer cells. In cancer, once a nest of cancer cells reaches a certain size, roughly 1 to 2 mm in diameter, the cancer cells must develop a blood supply in order for the tumor to grow larger as diffusion is not sufficient to supply the cancer cells with enough oxygen and nutrients. Thus, inhibition of angiogenesis by the inhibition of kinases involved in angiogenesis is expected to halt the growth of cancer cells.
One class of compounds that inhibit angiogenesis, inhibit the growth of tumors, treat cancer, modulate cell cycle arrest, and/or inhibit kinases such as Ras, Raf mutant B-Raf, VEGFR2 (KDR, Flk-1), FGFR2/3, c-Kit, PDGFRβ, CSF-1R is the class of compounds known as benzimidazolyl pyridyl ethers. Methods for the synthesis and use of various benzimidazolyl pyridyl ether compounds have been disclosed in WO 2003/082272 and WO 2005/032458, in U.S. Provisional Application Nos. 60/712,539 filed on Aug. 30, 2005; 60/731,591 filed on Oct. 27, 2005; 60/774,684 filed on Feb. 17, 2006; 60/713,108 filed on Aug. 30, 2005, and 60/832,715, filed Jul. 21, 2006, and in the U.S. utility application entitled “Substituted Benzimidazoles And Methods Of Their Use,” filed Aug. 30, 2006 (U.S. Ser. No. 11/513,959), and the U.S. utility application entitled “Substituted Benzimidazoles And Methods Of Preparation,” filed Aug. 30, 2006 (U.S. Ser. No. 11/513,745), the entire disclosures of which are herein incorporated by reference for all purposes. Despite the excellent biological activity shown by benzimidazolyl pyridyl ethers, challenges in formulating this class of compounds exist due to the low water solubility of the compounds at physiological pH.